With 300,000 yearly new cases worldwide, profound morbidity, and poor survival, oral cancer needs new treatment approaches, including prevention and early detection. Chemoprevention is a promising approach already showing potential for controlling breast, colon and prostate cancer. This P01 is an international, synergistic collaboration against the global threat of oral cancer, combining the rich patient base, novel tumor registry for population-based study and clinical, pathologic and biologic expertise of investigators from the Nordic region, the expertise in translational prevention, including molecular study of carcinogenesis and genetic susceptibility, statistical analyses of multiple biomarkers, and pharmacology, of the head and neck cancer research team at M. D. Anderson Cancer Center, and the profound expertise in COX2 and EGFR/HER2 signaling pathways by collaborators at Cornell University. The overall objectives of our program project are to help control the incidence of oral cancer, elucidate the biology of COX-2 and EGFR/HER2 signaling in and the impact of agents targeting these pathways on oral carcinogenesis, and elucidate the molecular biology and risk of oral cancer and the pharmacogenomic profiles of high-risk oral premalignant lesion (OPL) patients with respect to preventive interventions directed at COX-2, EGFR and HER2, all 3 targets validated in neoplasia with FDA approved molecular targeting drugs. To accomplish these goals we propose to carry out a phase-III randomized controlled trial (RCT) integrating molecular studies. Project 1 (Oral Cancer Prevention with Molecular Targeting Therapy) is a population-based RCT testing Celecoxib and EKB-569 in a 2 X 2 factorial design in extremely high-risk patients with aneuploid OPLs who have a >70% 3-year risk of developing biologically aggressive oral cancer. The rationale for the intervention includes the fact that in oral carcinogenesis both targets/pathways are activated, and preclinical models indicate anti-tumor activity of the single agents and enhanced activity of the combination. Projects 2-4 are tightly linked to the RCT. Project 2: Targeting COX-2 and EGFR Signaling in Oral Carcinogenesis; Project 3: Molecular Defects in Oral Carcinogenesis; Project 4: Molecular Epidemiology and Pharmacogenetics in Oral Carcinogenesis. The Cores (Administration, Biostatistics/Data Management, and Biospecimen, Pathology, Pharmacology) are also included to provide the structure and expertise required for the successful integration and execution of these studies. The new clinical and mechanistic insights into oral cancer gained in this program will be highly relevant to other tumor types, such as colorectal cancer.